Vascular occlusion by neutrophil extracellular traps in COVID-19
Moritz Leppkes, Jasmin Knopf, Elisabeth Naschberger, Aylin Lindemann, Jeeshan Singh, Irmgard Herrmann, Michael Stürzl, Léonie A. N. Staats, Aparna Mahajan, Christine Schauer, Anita N. Kremer, Simon Völkl, Kerstin Amann, Katja Evert, Christina Falkeis, Andreas Wehrfritz, Ralf J. Rieker, Arndt Hartmann, Andreas E. Kremer, Markus F. Neurath, Luis E. Muñoz, Georg Schett, Martin Herrmann
Abstract
BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.